Discovery of γ-secretase inhibitors efficacious in a transgenic animal model of Alzheimer's disease

被引：24

作者：

Asberom, Theodros

Zhao, Zhiqiang

Bara, Thomas A.

Clader, John W.

Greenlee, William J.

Hyde, Lynn A.

Josien, Hubert B.

Li, Wei

McPhail, Andrew T.

Nomeir, Amin A.

Parker, Eric M.

Rajagopalan, Murali

Song, Lixin

Wong, Gwendolyn T.

Zhang, Lili

Zhang, Qi

Pissarnitski, Dmitri A.

机构：

[1] Schering Plough Res Inst, Dept Chem Res, Kenilworth, NJ 07033 USA

[2] Schering Plough Res Inst, Dept Cent Nervous Syst, Kenilworth, NJ 07033 USA

[3] Duke Univ, Dept Chem, Durham, NC 27708 USA

[4] Schering Plough Res Inst, Dept Drug Metab & Pharmacokinet, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 02期

关键词：

Alzheimer's disease; gamma-secretase inhibitors; Kulinkovich reaction;

D O I：

10.1016/j.bmcl.2006.10.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce A beta levels in TgCRND8 mice after a single PO dosing at 30 mpk. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：511 / 516

页数：6

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